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PURPOSE: To investigate the use of two sequential courses of high-dose chemotherapy and peripheral blood progenitor cell (PBPC) transplant as initial therapy for patients with untreated metastatic breast cancer. The goal of the study was to maximize treatment intensity through the use of two non-cross-resistant regimens, each equal in intensity to that used in single transplants. METHODS: PBPC were collected after a course of granulocyte colony-stimulating factor (G-CSF) only or of cyclophosphamide, etoposide, and G-CSF. The first transplant regimen consisted of thiotepa (600 mg/m2), cyclophosphamide (6000 mg/m2), and carboplatin (800 mg/m2). After recovery from the first transplant, responding patients received a second course of therapy consisting of busulfan (16 mg/kg) and etoposide (60 mg/kg). RESULTS: Forty-four patients were enrolled. Five patients did not proceed to transplantation due to tumor progression during PBPC mobilization. Five patients achieved complete response after the first transplant, and 14 were in complete remission at the end of the therapy. Six patients remain free of disease after a median followup of 22 months (range 12-27+ months). The 2-year event-free survival for complete responders is 25.4% (standard error 14.4%). Engraftment was prompt, with a median of 8 and 13 days, respectively, to reach a neutrophil count of 500/mm3 and a platelet count of 50,000/mm3. As a result of the gastrointestinal toxicity of the first course, the median interval between transplants was 68 days. The toxicities of the second transplant course were principally hepatic and muco-cutaneous. Hepatic veno-occlusive disease occurred in 12 patients and was a contributor to the death of three. CONCLUSIONS: Rapid hematologic recovery achieved with PBPC made possible the administration of two courses of high-dose chemotherapy without compromising the intensity of either transplant regimen. The adverse effects of the second course, however, were substantially higher than predicted. The outcome of patients achieving a complete response is promising. Overall, the antitumor benefit of this approach in patients with previously untreated metastatic disease was not superior to that achieved with single transplants in patients responding to standard-dose chemotherapy.

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Recent developments in cell fixation, quantitative immunocytochemistry, and flow cytometry allow for the quantification of a variety of oncoproteins and other proliferation-associated antigens in both fresh and archival pathology material. These studies provide evidence that the standard tissue deparaffinization/dissociation technique significantly reduces the amount of c-myc oncoprotein remaining for analysis. To examine the factor(s) responsible for this observation, individual variables of the deparaffinization/dissociation technique including type of fixative, pepsin concentration, pepsinization times, pH, and exposure to organic solvents were examined in HeLa-S3 cells. The cells were stained with monoclonal antibodies either to the c-myc oncoprotein or to p105, a prolifera-tion-associated nuclear antigen. Protein-levels were measured on the basis of anti-c-myc or anti-p105 immunofluorescence by flow cytometry and were found not be affected significantly by type of fixative, exposure to organic solvents, acid pH solution, or mechanical disruption. Levels of c-myc oncoprotein were reduced by over 50%, however, when cells were exposed to 0.5% pepsin, whereas p105 was more resilient with only an approximately 7% reduction following the same treatment. Thus, careful examination of aspects of the deparaffinization/dissociation technique appears to be a necessary prerequisite for quantification of specific nuclear proteins from dissociated tissue specimens.

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The status of adjuvant therapy for colon cancer recently was clarified through the use of an innovative statistical evaluation of the existing published data. Even without including the NSABP results, meta-analysis formalized the long-held subjective impression that adjuvant treatment does not worsen patient outcome but, rather, consistently tends to improve it. It is important to recall that even small advantages for therapy of a common disease will have a major public health impact. A review of the results of adjuvant therapy in colon cancer thus far leads to suggestions for future directions, several of which already have been put into practice. Clearly, large-scale cooperative trials are necessary, not only to detect the subtle survival benefits of existing adjuvant therapies, but also to allow for meaningful subgroup analysis. Additional techniques for identifying and quantifying prognostic variables will aid in this latter effort. For example, flow cytometric DNA content analysis is currently in progress on patient specimens from several of the recently completed adjuvant trials, including those conducted by ECOG and NSABP. Not only will such analysis clarify the prognostic relevance of tumor ploidy and proliferative activity but, more importantly, it may identify subsets of patients who derive particular benefit from adjuvant treatment. Lastly, the need for more effective therapies is obvious. The current adjuvant trials employ agents or combinations of agents that hold some promise based on their activity in preliminary trials. However, significant progress will have to await the introduction of new agents with greater activity against colon cancer, and improvement in our understanding and use of specific immunotherapy.

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Paraffin-embedded surgical specimens from 120 patients who underwent resections for primary untreated colonic adenocarcinoma were examined for proliferative activity, DNA aneuploidy, DNA index, and the proportion of aneuploid cells by flow cytometry. The results were correlated with survival times and clinical characteristics of the patients. The presence of metastases, both distant and restricted to local lymph nodes, was found to be a more potent adverse prognostic indicator than any DNA flow cytometry-derived parameter. Additional analyses were performed following stratification of patients into two groups on the basis of presence or absence of metastases. Analysis of 60 patients without metastatic involvement revealed a significant correlation between high proliferative activity, defined as more than 20% of cells in S-phase, and DNA aneuploidy. In fact, high proliferative activity was shown to be a more powerful adverse prognostic indicator in relation to survival than DNA aneuploidy in these cases after multivariate analysis. These results suggest that differences in proliferative activity may be an important biologic factor operative in the variable prognosis seen in colonic adenocarcinoma. In addition, they re-emphasize the importance of stratifying patients into groups based on metastatic involvement when evaluating other possible prognostic features in this disease.

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